16: Studies for Neurologic Evaluation

Continued improvements in neuroimaging and neuromonitoring have added insight into the developing brain and helped the clinician to identify infants at risk for poor neurologic outcome. However, available techniques continue to be limited in their ability to predict neurodevelopmental outcomes accurately. Moreover, given the enormous plasticity of the neonate's brain, even significant detectable defects may result in “normal” neurodevelopmental outcomes. Nevertheless, imaging and monitoring modalities hold future promise in assisting clinicians to better identify patients at risk for neurodevelopmental sequelae.

1. Ultrasonography

   1. Definition. Using the bone window of a fontanelle, sound waves are directed into the brain and reflected according to the echodensity of the underlying structures. The reflected waves are used to create 2- and 3-dimensional images.

   2. Indication. Ultrasonography is preferred for identification and observation of germinal matrix/intraventricular hemorrhage and hydrocephalus and is valuable in detecting midline structural abnormalities, hypoxic-ischemic injury, subdural and posterior fossa hemorrhage, ventriculitis, tumors, cysts, and vascular abnormalities. Ultrasonography of the developing cingulate sulcus has been suggested to reflect gestational age (see sample studies in Chapter 11).

   3. Method. A transducer is placed over the anterior fontanelle, and images are obtained in coronal and parasagittal planes. The posterior fontanelle is the preferred acoustic window for the imaging of the infratentorium, including brainstem and cerebellum. Advantages include high resolution, convenience (performed at the bedside), safety (no sedation, contrast material, or radiation), noninvasiveness, and low cost. Disadvantages include the lack of visualization of nonmidline structures, especially in the parietal regions, and the lack of differentiation between gray and white matter.

   4. Results. The integrity of the following structures may be evaluated with ultrasonography: all 4 ventricles, the choroid plexus, caudate nuclei, thalamus, septum pellucidum, and corpus callosum.

2. Doppler ultrasonography

   1. Definition. Doppler ultrasonography also uses a bone window to direct sound waves into the brain. Moving objects (eg, red blood cells) reflect sound waves with a shift in frequency (Doppler shift) that is proportional to their speed. These changes are measured and expressed as the pulsatility index and resistance index (RI). The angle of the probe in relation to the flow affects the Doppler shift and requires exact standards for serial measurements.

   2. Indication. Knowing the cross-section of the vessel (area), Doppler ultrasonography can provide information on cerebral blood flow (CBF) and resistance. CBF (cm³/time) = CBF velocity (cm/time) × Area (cm²) Doppler ultrasonography is of clinical value in states of cessation of CBF (eg, brain death or cerebrovascular occlusion), states of altered vascular resistance (eg, hypoxic-ischemic encephalopathy, hydrocephalus, or arteriovenous [AV] malformation), and ductal steal syndrome.

   3. Method. Combined with conventional ultrasonography to identify the blood vessel, Doppler ultrasonography produces a color image indicating flow (red, toward the transducer; blue, away from the transducer). CBF velocity is measured as the area under the curve of velocity waveforms. Small body weight and low gestational ages negatively influence the success rate in visualizing intracranial vasculature. Contrast-enhanced ultrasonography with injection of gas-filled microbubbles (size of red cells) may offer improved cerebral perfusion measurement in the future.

   4. Results. Doppler ultrasonography measurements can be compared with age-adjusted norm values for systolic, end-diastolic, and mean flow velocity. Serial measurement of CBF and RI may be helpful in following lesions associated with increased cerebral pressure such as determining the need for a ventriculoperitoneal shunt in progressive hydrocephalus.

3. Computed tomography (CT)

   1. Definition. Using computerized image reconstruction, CT produces 2- and 3-dimensional images of patients exposed to ionizing radiation.

   2. Indication. CT is the preferred tool for evaluation of the posterior fossa and nonmidline disorders (eg, blood or fluid collection in the subdural or subarachnoid space) as well as parenchymal disorders. It is also helpful in the diagnosis of skull fractures.

   3. Method. The patient is advanced in small increments in a scanner, and images (cuts) are obtained. Cerebral white matter (more fatty tissue in myelin sheaths around the nerves) and inflammation appear less dense (blacker) than gray matter. Calcifications and hemorrhages appear white. If a patient receives contrast material, blood vessels and vascular structures (eg, falx cerebri and choroid plexus) appear white. Spaces containing cerebrospinal fluid are clearly shown in black, making it easy to identify diseases that alter their size and shape. Bones also appear white but are poorly defined, and details are better evaluated in a “bone window.” Disadvantages include the need for transportation and sedation, the potential for hypothermia, and radiation exposure.

   4. Results. CT provides detailed information on brain structures not accessible by ultrasonography and is superior to magnetic resonance imaging (MRI) in the diagnosis of intracranial calcifications. Caution should be exerted when considering the use of multiple diagnostic CT studies given the high exposure to ionizing radiation in infancy, which can play a role in future development of malignancies.

4. Magnetic resonance imaging (MRI)

   1. Definition. Inside a strong magnetic field, atomic nuclei with magnetic properties (hydrogen protons being most common) align themselves and emit an electromagnetic signal when the field is terminated and the nuclei return to their natural state. Computers reconstruct the signal into 2-dimensional image cuts. A variety of contrasts can be obtained in MRI and include T1- and T2-weighted imaging (reflecting 2 relaxation time constraints, longitudinal and transverse, respectively), diffusion-weighted imaging (DWI), blood-oxygen-level-dependent (BOLD) imaging, and proton-density weighted imaging. In functional MRIs (fMRI), such as BOLD and DWI, underlying brain physiology is reflected in the created images.

   2. Indication. MRI is the preferred tool for a number of brain disorders in the neonate that are difficult to visualize by CT, such as disorders of myelination or neural migration, ischemic or hemorrhagic lesions, agenesis of the corpus callosum, AV malformations, and lesions in the posterior fossa and the spinal cord. Diffusion-based MRI is the most sensitive to acute brain injury in the first week after injury. Conventional T1- and T2-weighted MRI is preferred after 1 week following the injury. Conventional MRI has been used at term equivalent or at the time of discharge from the hospital to predict neurologic outcome.

   3. Method. The patient is advanced in small increments in a scanner, and images (cuts) are obtained. Gray matter appears gray, and white matter, white. Cerebrospinal fluid and bones appear black; however, the fat content in the bone marrow and the scalp appear white. In T1 and T2 MRI, fluid may appear dark or bright, depending on the type of weighted image. Advantages of MRI include the ability to identify normal and pathologic anatomy without ionizing radiation and insight into neurologic prognosis. Disadvantages include the need for transportation, sedation, a ferro-magnetic free environment, the potential for hypothermia, and difficulties in monitoring during the procedure. Ventilated infants pose a special problem, and ferro-magnetic free MRI incubators have been developed and used to help prevent motion artifact, provide improved cardiorespiratory monitoring, maintain temperature and fluid status, and improve image quality by using built-in head coils.

   4. Results. MRI provides high-resolution images of the brain with exquisite anatomic detail and allows diagnosis of a number of illnesses easily missed by CT. The temporal development of the prenatal brain, including the emergence of sulci and gyri and the myelination process, has been described, allowing for a more meaningful interpretation of MRI in premature infants. Quantitative volumetric MRI has been used to demonstrate the effects of postnatal dexamethasone on cortical gray matter volume and to help provide long-term prognosis for neurologic outcome. Diffusion-weighted MRI can be used in the early diagnosis of perinatal hypoxic ischemic encephalopathy at any stage of development. fMRI promises new insights into the functional reorganization of the brain after injury. Diffusion tensor imaging (DTI) may demonstrate direction and integrity of neural fiber tracks through 3-dimensional diffusion of water molecules along the longitudinal axis of myelinated axons. Newer magnetic resonance spectroscopy allows the study of metabolic mechanisms through quantitative measurements of certain metabolites.

5. Near-infrared spectroscopy (NIRS)

   1. Definition. Light in the near-infrared range can easily pass through skin, thin bone, and other tissues of the neonate. At selected wavelengths, light absorption depends on oxygenated and deoxygenated hemoglobin as well as oxidized cytochrome aa 3, allowing for qualitative measurements of oxygen delivery, cerebral blood volume, and brain oxygen availability and consumption.

   2. Indication. Although NIRS is not widely used, it has potential as a bedside tool to follow cerebral oxygen delivery or CBF. It is a useful technique to assess the effects of new treatments and common interventions (eg, endotracheal suction, continuous positive airway pressure) on cerebral perfusion and oxygenation.

   3. Method. A fiberoptic bundle applied to the scalp transmits laser light. Another fiberoptic bundle collects light and transmits it to a photon counter.

   4. Results. NIRS allows qualitative determination of oxygen delivery, cerebral blood volume, and oxygen consumption. In intubated infants, NIRS has been used to identify pressure-passive cerebral circulation, a condition associated with a 4-fold increase in periventricular leukomalacia and severe intraventricular hemorrhage.

1. Electroencephalogram (EEG)

   1. Definition. An EEG continuously captures the electrical activity between reference electrodes on the scalp. In the neonatal period, cerebral maturation and development result in significant EEG changes during different gestational ages that must be considered when interpreting results.

   2. Indication. Indications include documented or suspected seizure activity, events with potential for cerebral injury (eg, hypoxic-ischemic, hemorrhagic, traumatic, or infectious), central nervous system (CNS) malformations, metabolic disorders, developmental abnormalities, and chromosomal abnormalities.

   3. Method. Several electrodes are attached to the infant's scalp, and the electrical activity is amplified and measured. Recordings can be traced on paper or can be saved electronically. EEG waves are classified into different frequencies: delta (1–3/s), theta (4–7/s), alpha (8– 12/s), and beta (13–20/s).

   4. Results. EEGs are sensitive to a number of external factors, including acute and ongoing illness, medications or drugs, position of the electrodes, and state of arousal. A number of abnormal findings can be documented on the EEG of the term and preterm infant, including the following:

      1. Abnormal pattern of development.

      2. Depression or lack of differentiation.

      3. Electrocerebral silence (“flat” EEG).

      4. Burst suppression pattern (depressed background activity alternating with short periods of paroxysmal bursts). Burst suppression patterns are associated with especially high morbidity and mortality and poor prognosis.

      5. Persistent voltage asymmetry.

      6. Sharp waves (multifocal or central).

      7. Periodic discharges.

      8. Rhythmic alpha-frequency activity.

2. Cerebral function monitor (CFM)/amplitude-integrated EEG (aEEG)

   1. Definition. CFM or an aEEG records a single EEG channel for each hemisphere. The range of the signal amplitude is displayed in microvolts. Discontinuity in the EEG results in a wider trace amplitude and a decreased lower margin.

   2. Indication. The cerebral function monitor allows for the fast identification of infants at risk for hypoxic-ischemic encephalopathy (HIE) and for assistance in the identification of clinical and subclinical seizure activity. In addition, it has been used to select patients for neuroprotective measures such as head or total-body cooling and has been useful in providing information on neurodevelopmental outcome in cases of HIE and intraventricular hemorrhages. Not available in all institutions, the aEEG has also been used in other conditions including metabolic disorders, congenital anomalies, extracorporeal membrane oxygenation, and postoperative monitoring.

   3. Method. Electrodes are attached to the scalp, and the aEEG channel is recorded at a speed of 6 cm/h. CFM cannot provide information on aEEG frequency or focal lesions. Unlike standard EEG, this technique requires fewer operating and interpreting skills, making it more readily available. The aEEG should be used in conjunction with the standard EEG to provide clinical information.

   4. Results. The aEEG provides information on the background pattern of electrical activity of the brain (Table 16–1), the presence or absence of the sleep-wake cycle (SWC), and/or the presence of epileptiform activity and other examples of neonatal aEEG patterns (Figure 16–1). After asphyxia, the occurrence of a moderately or severely abnormal aEEG trace has a positive predictive value >70% for abnormal neurologic outcome. For instance, burst suppression, low voltage, and flat trace in the first 12–24 hours after injury is associated with a poor prognosis. SWC returning before 36 hours is associated with good outcome and after 36 hours is associated with bad outcome.

3. Peripheral nerve conduction velocity

   1. Definition. Nerve conduction velocity allows the diagnosis of a peripheral nerve disorder by measuring the transmission speed of an electrical stimulus along a peripheral (median, ulnar, peroneal) nerve. Because of smaller nerve fiber diameters affecting the nerve transmission speed, neonates have a lower nerve conduction velocity than adults.

   2. Indication. In the weak and hypotonic neonate, nerve conduction velocity is an important tool in diagnosing a peripheral nerve disorder.

   3. Method. A peripheral nerve is stimulated with a skin electrode, and the corresponding muscle action potential is recorded with another skin electrode. To determine the nerve conduction alone (as opposed to nerve conduction, synaptic transmission, and muscle reaction), the nerve is stimulated at 2 points, and the resulting muscle response times are subtracted. The distance between the 2 points of stimulation divided by the time difference equals the nerve conduction velocity.

   4. Results. Nerve conduction velocities are prolonged in disorders of myelination and in axon abnormalities and may have potential clinical value in combination with other tests (eg, muscle biopsy or electromyogram) in these disorders. Initially, infants with anterior horn cell disorders (eg, Werdnig-Hoffmann paralysis) have normal nerve conduction but may demonstrate decreased velocity later in the course. Neuromuscular junction and muscle disorders do not alter nerve conduction velocity. This test is also used for gestational age assessment.

4. Evoked potentials. An evoked potential is an electrical response by the CNS to a specific stimulus. Evoked potentials are used to evaluate the intactness and maturity of ascending sensory pathways of the nervous system and are relatively unaffected by state, drug, or metabolic effects.

   1. Auditory evoked potential (AEP)

      1. Definition. An AEP is an electrical response by the CNS to an auditory stimulus.

      2. Indication. Brainstem AEPs may be used to detect abnormalities in threshold sensitivities, conduction time, amplitudes, and shape and may be useful as a hearing screen in high-risk infants.

      3. Method. Although neonates respond to an auditory stimulus with brainstem as well as cortical evoked responses, the latter are variable, depending on the state of arousal, and thus are difficult to interpret. As a result, AEPs (generated by a rapid sequence of clicks or puretones) traveling along the eighth nerve to the diencephalon are recorded by an electrode over the mastoid and vertex as brainstem AEPs, amplified and digitally stored. The shape (a series of waves) and latency of brainstem AEPs depend on gestational age. This technique is sensitive to movement and ambient noise.

      4. Results. Injuries in the peripheral pathway (middle ear, cochlea, and eighth nerve) result in an increased sound threshold and an increase in latency of all waves, whereas central lesions cause only increased latency of waves originating from distal (in relation to the lesion) structures. Brainstem AEPs are used to demonstrate disorders of the auditory pathways caused by hypoxia-ischemia, hyperbilirubinemia, infections (eg, cytomegalovirus or bacterial meningitis), intracranial hemorrhage, trauma, systemic illnesses, drugs (eg, aminoglycoside or furosemide), or a combination of these. In low birthweight infants, brainstem AEPs have a high false-positive rate secondary to known gestational differences (longer latency, decreased amplitude, and increased threshold in preterm infants). Up to 20–25% of infants in the neonatal intensive care unit have abnormal (failed) tests, and most have normal tests at 2–4 months. In asphyxiated infants, abnormal brainstem AEPs are associated with neuromotor impairments. Because infants with congenital infection and persistent pulmonary hypertension may experience progressive hearing loss, they require serial hearing evaluations even if results are normal.

   2. Visual evoked potential (VEP)

      1. Definition. A VEP is an electrical response by the CNS to a visual stimulus.

      2. Indication. A VEP may provide information on disorders of the visual pathway and has been used as an indicator for cerebral malfunctioning (eg, hypoxia).

      3. Method. An electrical response to a visual stimulus (eg, light flash in neonates or checkerboard pattern reversal in older children) is measured via a surface electrode. The electrical response is complex and undergoes significant developmental changes in the preterm infant.

      4. Results. When corrected for conceptional age, visual evoked responses allow the detection of various visual pathway abnormalities. Although generalized insults such as severe hypoxemia may result in temporary loss of visual evoked responses, local abnormalities may have similar results (eg, compression of the pathway in hydrocephalus). Persistent visual evoked response abnormalities in postasphyxiated infants have been strongly correlated with poor neurologic outcomes. Although VEPs may aid in the prognosis of long-term neurodevelopmental outcomes, they may not be helpful in predicting blindness or loss of vision. Improvements in visual evoked responses have also been applied to determine the success of interventions such as a ventricular-peritoneal shunt. The prognostic value in preterm infants is controversial.

   3. Somatosensory evoked potential (SEP)

      1. Definition. An SEP is an electrical response by the CNS to a peripheral sensory stimulus.

      2. Indication. SEPs allow insight into disorders of the sensory pathway (peripheral nerve, plexus, dorsal root, posterior column, contralateral nucleus, medial lemniscus, thalamus, and parietal cortex).

      3. Method. SEPs have been recorded over the contralateral parietal scalp after providing an electric stimulus to the median or the posterior tibial nerve. SEPs are technically more difficult to obtain than auditory brainstem evoked potentials and are age dependent, with significant changes occurring in the first months of life.

      4. Results. SEPs may allow evaluation of peripheral lesions such as spinal cord trauma and myelodysplasia as well as cerebral abnormalities such as hypoxia, ischemia, hemorrhage, hydrocephalus, hypoglycemia, and hypothyroidism. SEP abnormalities in term infants have a high positive predictive value for neurologic sequelae and abnormal neurodevelopmental outcome. The significance of SEP remains controversial in the preterm infant.

1. Definition. The clinical neurodevelopmental examination combines the assessment of posture, movement, extremity and axial muscle tone, deep tendon reflexes, pathologic reflexes (eg, Babinski sign), primitive (or primary) reflexes, cranial nerve and oromotor function, sensory responses, and behavior by an experienced clinician.

2. Indication. All infants should undergo a brief neurologic examination, including tone and reflex assessment, as part of their initial physical examination. A more detailed neurodevelopmental examination should be performed on high-risk infants. Important risk factors include prematurity, hypoxic-ischemic encephalopathy, congenital infection, meningitis, significant abnormalities on neuroimaging studies (eg, intraventricular hemorrhage, ventricular dilatation, intraparenchymal hemorrhage, infarct, or cysts), and feeding difficulties.

3. Method. The experienced clinician should examine the infant when stable, preferably during the recovery phase. However, the examination may also be quite useful when performed serially, as with hypoxic-ischemic encephalopathy. The infant's state of alertness may affect many responses, including sensory response, behavior, tone, and reflexes. Normal findings change according to age (actual and postconceptional).

   1. The full-term neonate. The normal full-term neonate has flexor hypertonia, hip adductor tone, hyperreflexia (may have unsustained clonus), symmetric tone and reflexes, good trunk tone on ventral suspension, some degree of head lag on pulling to a sitting from a supine position with modulation of forward head movement, presence of pathologic (eg, Babinski sign) and primitive reflexes (eg, Moro, grasp, and asymmetric tonic neck reflexes), alerting to sound, visual fixation, and a fixed focal length of 8 in.

   2. The preterm neonate. Before 30 weeks' postconceptional age, the infant is markedly hypotonic. Extremity flexor and axial tone and the reflexes emerge in a caudocephalad (ie, lower to upper extremity) and centripetal (ie, distal to proximal) manner. Visual attention and acuity improve with postconceptional age. The extremely preterm infant can suck and swallow, but coordination of suck with swallow occurs at ∽32–34 weeks' postconceptional age. Flexor tone peaks at term and then becomes decreased in a caudocephalad manner. In comparison with full-term neonates, preterm infants at term have less flexor hypertonia, more extensor tone, more asymmetries, and mild differences in behavior.

4. Results. Abnormalities on neurodevelopmental examination include asymmetries of posture or reflexes (especially significant if marked or persistent), decreased flexor or extremity tone or axial tone for postconceptional age, cranial nerve or oromotor dysfunction, abnormal sensory responses, abnormal behavior (eg, lethargy, irritability, or jitteriness), and extensor neck, trunk, or extremity tone. A normal neonatal neurodevelopmental examination is reassuring, but an abnormal examination cannot be used to diagnose disability in the neonatal period. The more abnormalities that are found on examination and the greater the degree of abnormality (eg, marked neck extensor hypertonia), the higher the incidence of later disability, including cerebral palsy and mental retardation.